Studies of ligand-gated ion channels, such as the N-methyl-D-aspartate receptor (NMDA-R)- and the nicotinic acetylcholine receptor (nAChR)- channel complexes, are important in mechanisms of drug abuse and are central to developing rational approaches for substance abuse treatments. Certain abused drugs, such as nicotine, directly affect these channels, whereas other agents (e.g., MK-801) that are capable of modifying chronic drug effects, also act through interactions with these channels. A nicotine withdrawal study assayed regional cerebral metabolic rates for glucose using the 2-deoxy-D-[1-[C-14]C]glucose technique to elucidate the effect of nicotinic antagonist, mecamylamine, in rats receiving chronic nicotine. Mecamylamine reversed the increase in cerebral glucose metabolism observed in animals that received nicotine without producing withdrawal signs lending support to the view that mecamylamine in combination with nicotine, is efficacious in treating nicotine dependence. Mecamylamine, itself, increased cerebral metabolism in the interpeduncular nucleus, a region in which nicotine also increases metabolism. This finding reinforces the complexity of this mecamylamine-nicotine interaction. We have continued our research on the physiological modulation of the NMDA-R by investigating the stimulatory effect of mono- and divalent cations on the glutamate recognition site. Using [H-3]CGP 39653 as the specific ligand for the glutamate site, we demonstrated that at physiological concentrations, cations, such as Ca+2, Mg+2, and Na+, increase Bmax for high-affinity binding sites and decrease Bmax for low affinity sites. These findings demonstrate that cations stimulate binding by converting glutamate sites from the low-affinity to high-affinity state. Recently we initiated a study of the structural-functional organization of nAChRs using novel radioactive ligands, [H-3]-epibatidine and its analogue [I- 125]IPH, (+/-)-exo-2-(2-[I-125]iodo-5-pyridyl)-7-azabicyclo[2.2.1] heptane, and demonstrated the presence of two binding sites on the nAChR-channel complex. The future characterization of these binding sites may offer possibilities for understanding the mechanism of action of nicotine and developing new drug therapies.